Development of novel aza-stilbenes as a new class of selective MAO-B inhibitors for the treatment of Parkinson’s disease

Knez, Damijan (avtor), Wang, Fen (avtor), Duan, Wen-Xiang (avtor), Hrast, Martina (avtor), Gobec, Stanislav (avtor), Cheng, Xiao-Yu (avtor), Wang, Xiao-Bo (avtor), Mao, Cheng-Jie (avtor), Liu, Chun-Feng (avtor), Frlan, Rok (avtor)

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Inhibitors of monoamine oxidase B (MAO-B) have shown promise in alleviating motor symptoms and reducing oxidative stress associated with PD. In this study, we report the novel use of an azastilbene-based compound library for screening human (h)MAO-B, followed by optimization of initial hits to obtain compounds with low nanomolar inhibitory potencies (compound 9, IC$_{50}$ = 42 nM) against hMAO-B. To ensure specificity and minimize false positives due to non-specific hydrophobic interactions, we performed comprehensive selectivity profiling against hMAO-A, butyrylcholinesterase (hBChE) and acetylcholinesterase (hAChE) — enzymes with hydrophobic active sites that are structurally distinct from hMAO-B. Docking analysis with Glide provided valuable insights into the binding interactions between the inhibitors and hMAO-B and also explained the selectivity against hMAO-A. In the cell-based model of Parkinson’s disease, one of the compounds significantly reduced rotenone-induced accumulation of reactive oxygen species. In addition, these compounds showed a protective effect against acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunction in PD model mice and reduced MPTP-induced loss of striatal tyrosine hydroxylase-positive neurons in the substantia nigra. These results make azastilbene-based compounds a promising new class of hMAO-B inhibitors with potential therapeutic applications in Parkinson’s disease and related neurodegenerative disorders.

• Jezik: Angleški jezik
• Ključne besede: neurodegenerative diseases, Parkinson’s disease, monoamine oxidase B, inhibitors, azastilbene, library
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: 22 str.
• Številčenje: Vol. 153, art. 107877
• PID: 20.500.12556/RUL-163955
• UDK: 616.831-003.8
• ISSN pri članku: 0045-2068
• DOI: 10.1016/j.bioorg.2024.107877
• COBISS.SI-ID: 211330051
• Datum objave v RUL: 14.10.2024

Gradivo je del revije

• Naslov: Bioorganic chemistry
• Skrajšan naslov: Bioorg. chem.
• Založnik: Elsevier
• ISSN: 0045-2068
• COBISS.SI-ID: 25099008

Licence

• Licenca: CC BY-NC 4.0, Creative Commons Priznanje avtorstva-Nekomercialno 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc/4.0/deed.sl
• Opis: Licenca Creative Commons, ki prepoveduje komercialno uporabo, vendar uporabniki ne rabijo upravljati materialnih avtorskih pravic na izpeljanih delih z enako licenco.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: zaviralci monoaminooksidaze B, azastilben, nevrodegenerativne bolezni, Parkinsonova bolezen